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MONOCLONAMONOCLONA
LL
ANTIBODIESANTIBODIES
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NT IB ODI ESNT IB ODI ES
PROTIENS SYNTHESIZED INPROTIENS SYNTHESIZED IN
BLOODBLOOD
IMMUNITY IN BLOODIMMUNITY IN BLOOD
BLOOD SERUMBLOOD SERUM
HETEROGENOUSHETEROGENOUS
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WH T RE m bs??H T RE m bs??
SPECIFIC LYMPHOCYTESPECIFIC LYMPHOCYTE
SINGLE TYPE AbSINGLE TYPE Ab
SPECIFICITY AGAINST SPECIFICSPECIFICITY AGAINST SPECIFICANTIGENANTIGEN
DIFFICULT IN MAINTAININGDIFFICULT IN MAINTAINING
CANCER CELLSCANCER CELLS
IMMUNOGLOBULINSIMMUNOGLOBULINS
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Contents:Contents:DiscoveryDiscovery
mAb !er"#ymAb !er"#y
Sr$c$re "%& '$%cio%Sr$c$re "%& '$%cio%
Pro&$cio%Pro&$cio% Ty#es Ty#es
mAb ec!%o(o)ymAb ec!%o(o)y
mAb !eorymAb !eory
A##(ic"io%sA##(ic"io%s
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♣♣DISCOVERDISCOVER
Y Y ♣♣
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TH E M GI C BU LLETH E M GI C BU LLET
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P UL EHR LICH UL EHR LICH
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Hu man-Mo use Hyb r!u man-Mo use Hyb r!
Ce ""se""s
GeorgesGeorges
KöhlerKöhler
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C#sar#sar
M"s$e n"s$e n
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Ne"s %a&e"s %a&
'er neer ne
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GREG WINTERGREG WINTER
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MONOCLONALMONOCLONAL
ANTIBODYANTIBODYTHERAPY THERAPY
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one specific antigenone specific antigen
stimulating the patient'sstimulating the patient'simmune systemimmune system
e.g.radioimmunotherapye.g.radioimmunotherapy
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STRUCTURESTRUCTUREANDAND
FUNCTIONSFUNCTIONS
OFOFMAb...MAb...
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IgG 150kDaIgG 150kDa
2 diff. chains2 diff. chainsight chain kappaight chain kappa
lam!dalam!da"apain #a! #c"apain #a! #c
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Tu mor ( e""s)) )u mor ( e""s)) )
$r!%2 &$2 !reast cancer $r!%2 &$2 !reast cancer
()*I%+DI$, recogni-e foreign ()*I%+DI$, recogni-e foreign ()*IG$),... ()*IG$),...
(!s are used to raise specific(!s are used to raise specificanti!odies on such surfaces ofanti!odies on such surfaces of
tumors//tumors//
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PRODUCTIONPRODUCTION
HYBRIDOMA CELLHYBRIDOMA CELL
PRODUCTIONPRODUCTION
RECOMBINANTRECOMBINANT
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HYBRIDOMAHYBRIDOMA
CELLCELL
PRODUCTION PRODUCTION
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RECOMBINANTRECOMBINANTAb PRODUCTIONAb PRODUCTION
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Repertoire cloning/phageRepertoire cloning/phage
display/yeast displaydisplay/yeast displayVirus/yeast used instead of MICEVirus/yeast used instead of MICE
Rapid cloning Ig gene segmentRapid cloning Ig gene segmentAbs having slightly diff. aminoAbs having slightly diff. amino
acid sequencesacid sequences
Ab of desired specificity areAb of desired specificity are
selectedselected
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T* e + , . on$s)))* e + , . on$s)))
specificity of (! to recogni-e (gspecificity of (! to recogni-e (g
sta!ilitysta!ilitytherapeutic efficacytherapeutic efficacy
detectiondetection
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TYPES OFTYPES OF!Abs!Abs
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MURINE MAbsMURINE MAbs
Initially &%ID+( technology asInitially &%ID+( technology as
usedused
"+%$,"+%$,
1.educed stimulation of cytotoity1.educed stimulation of cytotoity
2.ild allergic reactions2.ild allergic reactions
3.anaphylactic shocks3.anaphylactic shocks
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CHIMERIC MAbsCHIMERIC MAbs
urine 4aria!le region fusedurine 4aria!le region fused
onto human constant regiononto human constant region
Kappa light chainIgG1 hea4yKappa light chainIgG1 hea4y
chain6(nti!odies 758 humanchain6(nti!odies 758 human
Increases serum half lifeIncreases serum half life
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HUMANI"ED MAbsHUMANI"ED MAbs
Grafting murine hyper4aria!le aminoGrafting murine hyper4aria!le amino
acid domains into human anti!odiesacid domains into human anti!odies
958 human origin958 human origin
&umani-ed anti!ody:parent murine&umani-ed anti!ody:parent murine
(!(!Introducing ;*(*I+), likeIntroducing ;*(*I+), like chain<chain<
shuffling= site<specific mutagenesis= $<colishuffling= site<specific mutagenesis= $<coli
mutator strains and others...mutator strains and others...
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HUMAN MAbsHUMAN MAbsransgenic miceransgenic mice ++
phage display librariesphage display libraries
*ransferring human genes into murine genome.*ransferring human genes into murine genome.*he mouse is then 4accinated against the human*he mouse is then 4accinated against the human
immunoglo!ulinimmunoglo!ulin
"hage display li!raries transforms murine (!s in"hage display li!raries transforms murine (!s in4itro into fully human (!s.4itro into fully human (!s.
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MAb Te#$no%o&'...MAb Te#$no%o&'...
>&I)(>&I)(Dr. a an= unnan uni4ersityDr. a an= unnan uni4ersity
"iece of paper test"iece of paper test
unda onoclonal *echnologyunda onoclonal *echnology
>ompany>ompany
(ID,= &epatitis %= &epatitis >= (ID,= &epatitis %= &epatitis >="rostrate >ancer= 4enereal disease"rostrate >ancer= 4enereal disease
and so on...and so on...
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!Ab!Ab
t$eo('t$eo('
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Antigen!"oreign invadersAntigen!"oreign invaders
Antibody!#atural defensesAntibody!#atural defenses
Monoclonal AntibodiesMonoclonal Antibodies
$rotect$rotect
diagnosediagnose
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$ure antibody prod.$ure antibody prod.
Immortal cellsImmortal cellsumor cell %ith mammalianumor cell %ith mammalian
cell fusioncell fusion& type of cell i.e. 'ybridoma& type of cell i.e. 'ybridoma
hence monoclonalhence monoclonal
Many (inds of cells)Many (inds of cells)
polyclonalpolyclonal
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C)n#e( t(e)t!entC)n#e( t(e)t!ent
%ind only to cancer cells%ind only to cancer cells,ho immunological response,ho immunological response
odificationodification
%ispecific anti!ody%ispecific anti!ody
(D$"*<anti!ody directed en-yme (D$"*<anti!ody directed en-yme
prodrug therapyprodrug therapy
(D>><anti!ody dependent cell<mediated (D>><anti!ody dependent cell<mediated
cytotoicitycytotoicity
( d th( d th
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